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Minutes of the Fourth Meeting - May 21, 2001

Cancer Advisory Panel for Complementary and Alternative Medicine (CAPCAM)

The Cancer Advisory Panel for Complementary and Alternative Medicine (CAPCAM) convened on May 21, 2001, at the Pooks Hill Marriott, Bethesda, Maryland. Richard Nahin, Ph.D., M.P.H., Executive Secretary of CAPCAM, called the meeting to order at 9:05 a.m.

On this page

  1. Call to Order and Meeting Procedures
  2. Introductory Remarks
  3. Virulizin
  4. Discussion
  5. Recommendations
  6. Rand Best Case Series for Cam Treatment of Cancer
  7. Update on NIH Initiatives for CAM and Cancer
  8. Public Comment
  9. Adjournment

CAPCAM Members Present

  • Michael Hawkins, M.D., Chair
  • Peter L. Choyke, M.D.
  • Ian D. Coulter, Ph.D.
  • David J. Hufford, Ph.D.
  • Ralph W. Moss, Ph.D.
  • Susan K. Quella, R.N.
  • Debasish Tripathy, M.D.
  • Jeffrey D. White, M.D, Ex-Officio Member

AD HOC Members

  • Xin Chen, M.D., Ph.D.
  • Susan Holloran
  • Leanna Standish, N.D., Ph.D.
  • James E. Williams

NIH Staff Present

  • Richard Nahin, M.P.H, Ph.D.
  • Marc Pitts, M.B.A
  • Mary Ann Richardson, Dr.PH
  • Stephen Straus, M.D.
  • Shan Wong, Ph.D.

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I. Call to Order and Meeting Procedures

The meeting was called to order by Richard Nahin, M.P.H., Ph.D., Executive Secretary of CAPCAM. Dr. Nahin reviewed the rules concerning confidentiality and conflict of interest, and polled the members for acceptance.

II. Introductory Remarks

Dr. Michael Hawkins, chair, asked members to introduce themselves. Dr. Hawkins then explained that the first presentation would be by Lorus Therapeutics, Inc. on Virulizin®, a cancer therapy. The committee would then focus on whether the treatment falls within the realm of CAPCAM; whether the work was promising enough to continue; and if so, whether CAPCAM should play a role.

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III. Virulizin

Dr. Jim Wright, president of Lorus Therapeutics, introduced the company and the history of Virulizin®. He explained that the goal of Lorus was to build the leading biopharmaceutical company specializing in research and development of efficacious therapies with low toxicity for management of cancer. He then explained that Virulizin®, which is extracted from bovine bile, was first introduced by a Romanian veterinarian in the 1980s who had noticed that certain animals, and certain animal organs, seemed resistant to cancer.

Dr. Donald Braum then discussed the cell biology behind Virulizin®. He explained that Virulizin® is a pyrogen-free, liquid, clinically non-toxic biological response modifier (BRM) that exerts its anti-tumor effects by enhancing the cell-mediated immune response to tumor cells. Virulizin® is obtained from bovine bile by a standardized process involving solvent extraction and heat hydrolysis and is provided for IM (intramuscular) injection. The immunostimulatory function of Virulizin® is achieved by direct macrophage activation. Virulizin® stimulates the production of TNF (tumor necrosis factor) in combination with LPS (lipopolysaccharide) from monocytes and macrophages. Its stimulatory function is not inhibited by prostaglandins, hence it is distinct from many other activators.

Dr. Braum then briefly introduced the pancreatic cancer study, which indicated that Virulizin® promoted a trend towards increased killing in the blood by monocytes. The company had also begun to see a trend towards increased blastogenic response, and an increase in lymphocyte-based killing. Dr. Braum reiterated that Virulizin® is a well-tolerated drug that does not contribute to patient morbidity. He also touched on the possibility of Virulizin® being effective in the treatment of other diseases, such as endometriosis and atypical micro bacterial infections.

Dr. Straus asked whether Virulizin® required organic and inorganic compounds; Dr. Chen asked for more information about the veterinarian who had the idea to use bile. Dr. Moss then inquired whether Lorus had looked at oral administration of Virulizin®, and the response was that although it could certainly be explored, it did not look like a promising mode of administration.

Dr. Aiping Young presented the information on pre-clinical animal testing. Virulizin® showed significant inhibition of growth of human tumors injected in mice. The results were most striking when Virulizin® was used in combination with standard chemotherapeutic drugs such as DTIC against melanoma, Gemcitabine against pancreatic adenocarcinoma, and Taxol against breast adenocarcinoma. In some studies, partial to total regressions of the cancer were observed during prolonged treatment periods. Both acute and chronic toxicity studies in mice indicated that Virulizin® injected intramuscularly was very well tolerated by the animals. Mutagenicity studies with Virulizin® were also negative.

Dr. Guy Ely then gave an overview of the Phase I/II and Phase II clinical trials of Virulizin®. The trials consisted of three studies -- CO1, CO2, and USO1 -- performed on cancer patients with solid tumors (108 patients); pancreatic cancer (61 patients); and malignant melanoma (52 patients). The general results included superior tolerance & safety, extension of median survival, and improved quality of life.

Meta-analysis of the three studies compared subjective responses to Virulizin® and Gemcitabine. Over a four week course, Virulizin® results were at least equal to Gemcitabine, but with better quality of life and less pain. A summary explained also that Gemcitabine patients were pre-selected for pain control; and it is already known that patients with less pain in pancreatic cancer have longer life span. The Gemcitabine patients were chosen only if pain was under control by 10 days.

Dr. Ely summarized the results of the meta-analysis conclusions for all three studies: the amount of adverse events were small; the most conservative estimates of survival were better with Virulizin® than in a similar patient population receiving Gemcitabine; the survival experience of Virulizin® patients was significantly better; the median survival rates were comparable; and the subjective response values were maintained for at least four weeks.

Ms. Quella asked which quality of life standards were used in the analysis. The answer was Spitzer.

Dr. Ely then explained his reasons for approaching CAPCAM. Lorus Therapeutics wishes to run a pivotal Phase III, open-label, multi-center, randomized study of Virulizin® administered intramuscularly (3 cc injections 3x per week) plus best supportive care, versus best supportive care alone in patients with advanced pancreatic cancer who have failed or are intolerant to chemotherapy. The goal is to understand Virulizin® better. The planned study would require about 250 patients and take approximately 2 ½ years to complete. The end points of the Phase III study would be survival, quality of life, and clinical benefits.

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IV. Discussion

Dr. Straus asked about a comparison to another study and the answer was addressed by Dr. Chen. Dr. Moss asked about the antioxidant qualities of ox bile. Dr. Braum stated that it hadn't been studied yet, although there are indications. Dr. Standish asked about possibly studying oral administration of Virulizin®. Dr. Wright and Dr. Young said that while that could be explored, Virulizin® made in other ways turned out to be toxic. The current process separates out toxic components, but must be administered through IM injection.

Dr. Hawkins then began the discussion on whether Virulizin® falls under the rubric of CAPCAM criteria. Ms. Holloran asked whether results for Virulizin® could be further quantified. Dr. Braum emphasized the issue of quality of life, as drugs for metastatic cancer are very difficult to tolerate. Dr. Moss said he'd love to see the drug approved and available, but he was having trouble conceiving of it as a so-called natural product. He wanted to be assured that supporting it wouldn't break purview. Dr. Hufford countered that the committee did not have strictly-defined criteria for what constitutes complementary and alternative medicine (CAM), and that he believed it fit. He also stated that the committee must be careful not to discount therapies because the science behind them is well-developed. Ms. Holloran asked that the committee look at CAM therapies not just by what they are, but how they act in patients. She stated that non-toxicity was an important criterion for CAM. Mr. Williams asked how a product of this type gets to this table, as that may give some indication of whether it is CAM or not. Dr. Nahin answered that Virulizin® was brought to CAPCAM's attention by the National Cancer Institute (NCI), which couldn't agree on whether or not it was CAM. Dr. Hawkins asked him to summarize the disagreement, and Dr. Nahin answered that the question revolved around how much of the product was natural and how much was processed. Mr. Williams asked if there are any pure products being tested, and Dr. Hawkins replied that there are some purer products, but not being tested by CAPCAM. Dr. Straus said that a pure product could be under our purview, and Dr. Hawkins pointed out that all products must be processed in some fashion to get quality controls and get them into clinical trials. Dr. Hawkins gave his opinion that he was comfortable with the mixture under discussion as CAM, and Dr. Coulter concurred, pointing out that this is always a grey area. Dr. Coulter also expressed that his real interest was in what CAPCAM could/should do to support this product.

Dr. Hawkins asked if there was further discussion regarding Virulizin® as CAM. Dr. White said he sees similarities with other CAM products, based on the bile originator. Ms. Holloran asked whether Virulizin® could be used as a preventative, and Dr. Braum answered that it should be possible in cases where there is a high prognosis of recurrence and long therapy is expected, such as endometriosis and HIV patients with a high likelihood of cancer. Dr. Hawkins pointed out that long-term administration is problematic if only IM injection is available. Ms. Holloran stated that using Virulizin® as a preventative would add to its value for CAPCAM, as conventional medicine has so little to address this. Dr. Moss pointed out that Virulizin® is a palliative, not a cure. But he added that he does consider it CAM. Dr. Hawkins then polled the members, and there was general agreement that Virulizin® could qualify as CAM.

Dr. Hawkins then directed the committee to consider what it could do to help. Dr. Moss emphasized that CAPCAM shouldn't jump in to give money when other money is available. Dr. Nahin pointed out that among the recommendations that they could make would be an RFA; helping Lorus Therapeutics apply for other monies, including applying through regular channels at NIH; requesting applications to aid research; helping as program officers to get a high-quality application for peer review; helping to set up the process for patients to apply for next trial.

Dr. Standish inquired as to who was currently funding the planned Phase III trial, to which Dr. Wright responded that they'd had trouble finding investors, because of the natural component of Virulizin®. In particular, their proprietary purification process wasn't enough to get funding - people worried about hoof and mouth, and other diseases. He asked whether CAPCAM had ideas to overcome this problem. Dr. Ely emphasized the amount of patients clamoring for this product, and their inability to provide it at this point. Dr. Ely explained that Lorus Therapeutics needed to attract a large pharmaceutical company for worldwide distribution, but the pharmaceuticals wanted a complete analysis of components, which would hold up a Phase III trial. Dr. Tripathy agreed that this was the Catch 22 of nonpurified products. Ms. Holloran said that this is an institutional problem, and a fundamental CAM problem, that those with disease feel an urgency that the institutions can't address. She asked how the committee could come to grips with this. Mr. Williams asked about the estimated cost of the Phase III trial, and Dr. Wright said $10 million. Dr. Hawkins agreed that a Phase III study was necessary and the time was right. Dr. Standish asked if it would be possible for project officers at NCCAM to produce a high quality RO1 application that could be co-funded by CAPCAM and NCI. Dr. White didn't think that was the most efficient route, and that other routes would provide more opportunity/push for drug. Dr. Hawkins recommended the Cancer Therapy Evaluation Program route instead, as CTEP is a scientific association and can more easily accommodate a cooperative group study. Dr Braum pointed out that the pancreatic cancer patient population may be too small for a cooperative group effort. Dr. White asked whether they could do a melanoma treatment in Phase III as well. Dr. Ely stated that the data is ready on pancreatic cancer, but not on other types, because as a small company they could only afford small clinical trials.

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V. Recommendations

Dr. Hawkins recommended that Dr. White contact CTEP to work on a solution to Lorus Therapeutics' problem. Dr. White added that his office at NCI has an active search out for Phase II and III clinical trials, for funding within this fiscal year, and that the application deadline is July 2. Dr. Tripathy pointed out that working through CTEP would allow for the trials to be open to any group, not only co-ops, and since Lorus already has several investigators ready with patients, this would let them still proceed. He also expressed some concern that supportive care alone may not be enough to attract patients. Ms. Holloran asked about the funding at CTEP, but Dr. Hawkins explained that the value of the program is as a mechanism to run trials. Dr. Standish asked if CTEP had any CAM experts on their panels, and Dr. White answered that some outside ad hoc members may have CAM experience, but that appropriate people are also added as necessary.

The committee voted to take a break (11:40) and resume at 12 noon. At noon, the committee resumed. Dr. Nahin passed a confidentiality statement for committee members to sign, and reminded members of the reimbursement travel expense sheet. He then introduced Dr. Coulter to talk about the Rand Best Case Series for CAM Treatment of Cancer.

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VI. Rand Best Case Series for Cam Treatment of Cancer

Dr. Coulter began by discussing the history of best case series studies. These studies have faced several obstacles: insufficient candidates and/or difficulty recruiting candidates; barriers in terms of economic costs, time, and know-how; legal regulations in attaining files and permissions; the challenges of varying office formats, result statistics, etc. The aim of the Rand project is to compile data for three CAM providers to determine if there is sufficient evidence for further study.

The methodology involves accessing the files of the CAM provider to identify best cases; contacting patients for permission; comparing with files from a patient's mainstream provider; reviewing cases for inclusion; and abstracting the data. Moreover, the RAND procedure involves a complete patient interview on health-related quality of life. The process relies on a mainstream medical provider to provide other documentation of diagnosis and treatment. In particular, it is important to obtain a histological confirmation; the starting date for CAM; well-documented CAM treatment; a record of exclusive CAM treatment; and a documented end-point (i.e. remission, reduction of tumor size, longevity, etc.). RAND has found that as an independent research provider, it has had more success in accessing files than other groups with potential conflicts of interest.

A previous best case series study was done by the National Foundation for Alternative Medicine in 1999. Of 73 cases, 27 met the inclusion criteria, and 20 cases were reviewed in the final report. RAND is reviewing this series and using it to eliminate problems. In this series, extended quality of life was the most common outcome criteria, with patients more than two standard deviations from the national statistics.

Dr. Coulter then went on to discuss the first RAND best case series site, a program for immuno-augmented therapy in the Bahamas. This therapy involved daily injections of human-processed blood based on the patients' immune systems, in an attempt to encourage anti-tumor activity while not inhibiting the immune system. At this site, there were 23 cases, 17 of which meet the inclusion criteria. The documentation of prior cancer treatment is fairly complete, as is the data on chronology of care. Standard protocol for immuno-augmentation therapy was used. The weakest documentation involves the immuno-augmentation therapy care, including the initiation date, but Dr. Coulter believes this can be recovered.

Dr. Moss pointed out that the survival statistics were very iffy. Dr. Coulter agreed, and noted that RAND will have its own statistician to assess results.

Dr. Coulter then briefly discussed the second site, a New York program to study pain therapies.

Ms. Holloran questioned the need for best case series. Dr. Nahin said that RAND was hired to try to provide the type of data that CAPCAM providers have said they need. If RAND can't get it, it may not be attainable. Dr. Coulter talked about the time involved, and the need to pick the programs in which this is attainable. Dr. Tripathy talked about needing to find a fairly cohesive group of patients. Dr. Coulter stated that their statistician asked for the same thing, and he agreed it's a problem. Dr. Hawkins posed the rhetorical question: what are we trying to learn from a best case series? He explained that CAPCAM needs finished studies to see if they are worth pursuing further, although none of these studies will be definitive, since only the best case examples will be used. But he said that trying to put statistical conclusions on this type of data would slow the process. Dr. Coulter agreed, saying that they just need good, promising cases that are documented. Dr. Hufford asked about prospective analysis studies, as they might be a way to get systematic data if best case study fails. Dr. Nahin added that they might make a good second phase after best case study. Dr. Moss explained that historically, one group of patients claimed something was a cure; and on the other side, fraud was claimed. The best case study is used to determine whether anything is there before running a clinical trial. The goal is to find plausibility only. Mr. Williams noted that patients are quite anxious to find out if anything is there.

Dr. Standish noted that most cancer patients are using CAM in a complementary way, and asked how they could assess the addition of CAM therapies. She wanted to know if there was a way to start investigating the efficacy of that. Dr. Coulter explained that they would need to look at observational studies to accomplish that. Dr. Standish noted that the conundrum would be defining the comparison group.

Dr. Hawkins announced that Dr. Coulter would give a further update on the RAND best case series study at the next CAPCAM meeting.

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VII. Update on NIH Initiatives for CAM and Cancer

Dr. Mary Ann Richardson presented an overview on current CAM cancer research at NCCAM.

There are two P50 NCCAM-funded cancer centers: Johns Hopkins and University of Pennsylvania. University of Pennsylvania is focused on hyperbaric oxygen head and neck cancers. Projects include post laryngectomy complications/quality of life; angiogenesis and tumor growth; cell adhesion; and nitric oxide synthesis. Johns Hopkins is focused on breast and prostate cancer, and the Johns Hopkins projects include oxidative stress in cells; natural products for pain (rodent model); Phase II PC SPES in prostate cancer; and prayer on breast cancer recurrence in Africa American women.

Approximately 22 investigator-initiated RO1 and R21 studies are currently underway, funded through 15 grants. Most of the RO1 and R21 projects are studying bio-pharmacologic and herbal products, but other areas of study include alternative system models, manipulation, energy, and mind-body work. Examples of projects include the following:

  • Distant healing for glioblastoma at the California Pacific Medical Center
  • Massage for cancer-related fatigue at the University of California - San Francisco Osher Center
  • Scutellaria baicalensis for skin cancer at Mt. Sinai
  • Mechanisms of herbal radiosensitization of glioma cells at California Pacific Medical Center
  • Ginkgo biloba to stabilize/prevent cancer at George Washington University
  • Shark cartilage as an angiogenesis inhibitor at Boston Children's Hospital
  • Soy isoflavones for prostate/breast/bone cancer at Stanford
  • Soy phytoestrogens for post menopause HRT at Wake Forest

Several trials are funded through the NCI established research networks and comprehensive cancer centers. A phase III trial of shark cartilage extract is underway at M.D. Anderson Cooperative Research Base and another evaluating a shark cartilage powder is being finalized for the North Central Cancer Cooperative group at Mayo. In addition, an evaluation of the Gonzalez complex nutritional regimen for pancreatic cancer is underway at Columbia.

New research may result from several initiatives and mechanisms for funding: program announcement for novel therapies for cancer treatment; supplements to the P30 comprehensive cancer centers; requests for applications for the frontier medicine, herb-drug interaction, integrative medicine, and end-of-life care initiatives; and the standard investigator initiated RO1-R21 mechanism.

Ms. Holloran asked how the quality of placebo massage could be assessed. Dr. Richardson acknowledged that this was a common problem for studies of massage and acupuncture and such, and explained how the problem was being addressed. Ms. Holloran then asked whether information on the CAM funded studies were in the public domain. Dr. Nahin stated that under the Freedom of Information Act, only abstracts were available, as long as there were proprietary and intellectual property issues. Nothing goes into the public domain until there is a published study.

Dr. White addressed the issue of cancer CAM information. There are seven summaries of research currently available on the website and by phone. A PDQ CAM editorial board is now forming to review these summaries before posting. The board will have a variety of expertise and meet about four times a year, with Dr. White as Editor-in-Chief.

Dr. White then addressed the new NCI CAM initiatives. A letter RFA for CAM cancer pilot projects in NCI-designated cancer centers was released, with a goal of supporting projects with a high likelihood of developing into successful RO1 applications; of facilitating the development of continuous CAM research programs; and of encouraging and supporting collaborations between strong conventional cancer researchers and CAM practitioners and researchers. This letter RFA received 21 responses.

Another new NCI CAM initiative was an announcement of March 21 regarding supplements to NCI's Cooperative Groups and Community Clinical Oncology programs for randomized Phase II and Phase III trials for CAM interventions in cancer. Letters of intent for this program are due June 1 and applications are due July 2.

A promotion plan for the best case series has included direct mail, interviews, journal ads, etc. As a result, the program has grown from 12 inquiries in 1999, which generated three submissions with one actual completed presentation; to 120+ inquiries between September and May of this year. Additionally, the time between inquiry and completion has shortened.

Dr. White then announced a new position opening for a nurse consultant in research, OCCAM, NCI. Applications are due by June 5. Dr. White stated that this person would be involved mainly in data collection and the real nuts and bolts of data assessment and coordination.

Dr. White then discussed the status of Practice Outcomes Monitoring and Evaluation projects involving insulin potentiation therapy; and the P Banerji Homeopathic Research Foundation in Calcutta, India. Dr. Tripathy asked whether special patient protocols were needed for this and other studies, and Dr. White responded that they have them wherever necessary.

Dr. White went on to discuss the status of three CAM cancer clinical trials: a randomized trial of phase III lung cancer patients in a study of a liquid shark cartilage product; a randomized trial of phase III breast and colorectal cancer patients with a powdered shark cartilage product; and the Kelley/Gonzalez Regimen study on pancreatic cancer at Columbia University. This study is ongoing but no longer randomized and needs patients.

A long discussion ensued about the Kelley/Gonzalez criteria and efficacy of study; and the potential dampening effect of a failure of this study. Dr. White noted that the eligibility criteria may be too strict. Although the study has been highly publicized, only about 10% of referrals qualify. Possible solutions were discussed without clear answers, since publicity has not been the problem. Dr. Straus noted that in the future, with best case series data, we can have other trials with easier recruitment of patients and less stringent criteria. Dr. Tripathy said that there was no need to throw out the whole process just because this case has been difficult. Dr. Moss made a general observation that although vast numbers of people use alternative medicine, many are unwilling to go through extensive, arduous therapies. Dr. Hawkins noted that most alternative cancer centers are vastly underused. Dr. Straus said, "Our ability to reach out and be open-minded about alternative therapies is constantly impugned by traditional medicine and others. We must press on, because this is groundbreaking and important." Dr. Hawkins made these the final comments.

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VIII. Public Comment

No public comments were made.

IX. Adjournment

The meeting was adjourned at 2:30 pm.

Certification: We hereby certify that, to the best of our knowledge, the foregoing minutes are accurate and complete.

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